Effectiveness of successive booster vaccine doses against SARS-CoV-2 related mortality in residents of long-term care facilities in the VIVALDI study

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused severe disease in unvaccinated long-term care facility (LTCF) residents. Initial booster vaccination following primary vaccination is known to provide strong short-term protection, but data are limited on duration of protection and the protective effect of further booster vaccinations. Objective To evaluate the effectiveness of third, fourth and fifth dose booster vaccination against SARS-CoV-2 related mortality amongst older residents of LTCFs. Design Prospective cohort study. Setting LTCFs for older people in England participating in the VIVALDI study. Methods Residents aged >65 years at participating LTCFs were eligible for inclusion if they had at least one polymerase chain reaction or lateral flow device result within the analysis period 1 January 2022 to 31 December 2022. We excluded individuals who had not received at least two vaccine doses before the analysis period. Cox regression was used to estimate relative hazards of SARS-CoV-2 related mortality following 1–3 booster vaccinations compared with primary vaccination, stratified by previous SARS-CoV-2 infection and adjusting for age, sex and LTCF size (total beds). Results A total of 13,407 residents were included. Our results indicate that third, fourth and fifth dose booster vaccination provide additional short-term protection against SARS-CoV-2 related mortality relative to primary vaccination, with consistent stabilisation beyond 112 days to 45–75% reduction in risk relative to primary vaccination. Conclusions Successive booster vaccination doses provide additional short-term protection against SARS-CoV-2 related mortality amongst older LTCF residents. However, we did not find evidence of a longer-term reduction in risk beyond that provided by initial booster vaccination.


Introduction
Long-term care facilities (LTCFs) in the UK were severely impacted by COVID-19 early in the pandemic [1]. As such, LTCF staff and residents were prioritised for primary vaccination against syndrome coronavirus 2 (SARS-CoV-2) starting in December 2020 [2] and for additional booster vaccinations.
We previously reported waning of protection against infection and severe outcomes following primary vaccination in LTCF residents from 84 days following second dose [3], with improvement in protection against severe outcomes observed following first booster vaccine dose [3] that remained after emergence of the Omicron variant [4]. The present study focuses on mortality because changes to UK testing policy in LTCFs within the period analysed make it challenging to analyse effects on SARS-CoV-2 infection incidence or evaluate hospital admissions. We aimed to produce an updated evaluation of the effectiveness of third, fourth and fifth dose booster vaccination against SARS-CoV-2 associated death amongst residents of LTCFs in England in 2022.

Methods
VIVALDI is a prospective cohort study investigating SARS-CoV-2, including residents and staff of LTCFs providing residential and/or nursing care for older people in England [5]. Following national guidelines, residents underwent monthly routine polymerase chain reaction (PCR) testing until end of March 2022, when policy switched to symptomatic and outbreak testing only. Residents of participating LTCFs aged >65 years were eligible for inclusion if they had at least one PCR or lateral flow device (LFD) result recorded within the analysis period 1 January 2022 to 31 December 2022. We excluded individuals who had not received at least two vaccine doses before the analysis period [4] because unvaccinated residents are substantially more likely to be receiving end of life care. Individuals with third vaccine dose recorded before 14 September 2021, fourth dose before 21 March 2022 and fifth dose before 5 September 2022 were excluded as these dates corresponded to national roll-out to residents. Individuals whose first test record was a positive result within 2022 were excluded, as they would have only been considered as under follow-up from time of infection. The analysis period was chosen to allow our prior estimates of vaccine effectiveness to be updated whilst retaining a period when asymptomatic testing was still in use in order to ascertain the cohort.
As previously we retrieved all available PCR and LFD results from the national testing programme through the COVID-19 Datastore. Test results and vaccination (National Immunisation Management Service) and mortality (Office for National Statistics) data from national records were linked to study participants using pseudo-identifiers based on National Health Service (NHS) numbers [3]. COVID-19 death was defined as death within 28 days of positive PCR or LFD test or with COVID-19 recorded as primary or secondary cause of death on the death certificate. The legal basis to access data is provided by Health Research Authority Confidentiality Advisory Group approval (21/CAG/0156). Ethical approval was obtained from South Central-Hampshire B Research Ethics Committee (20/SC/0238). SARS-CoV2 serological test results for IgG antibodies to nucleocapsid protein (ARCHITECT system (Abbott, Maidenhead, UK)) were linked in a subset of participants who consented to blood sampling specifically for the VIVALDI study [6].
We used Cox regression models to derive adjusted hazard ratios (HRs) for risk of SARS-CoV-2 linked death. Vaccination status was included as time-varying covariable, with reference category two vaccine doses and categorical exposure groups following doses 3-5 (full details Appendix S1: Further details of statistical analysis). Baseline hazard was defined over calendar time. Analysis was stratified by evidence of SARS-CoV-2 infection prior to risk period, based on combined PCR and LFD results, hospital admission records and nucleocapsid antibody results where available. We adjusted for sex (binary variable), age (five-knot restricted cubic spline term) and LTCF size (number of beds, linear term).

Results
Analysis included 13,407 residents from 327 LTCFs ( Figure S1 Table S1). A similar pattern was observed following fourth and fifth dose vaccination, although confidence intervals for HRs were wider for fourth dose beyond 84 days and for fifth dose (Figure 2d) because of lower available follow-up time and lower incidence of SARS-CoV-2 infection in the latter half of 2022. Residents with known infection prior to analysis period were at reduced risk of death relative to those without prior infection (0.55,0.28-1.08; amongst those with two-dose vaccination). Within this group, the pattern of further protection from booster vaccination was similar to those without known prior infection, although there is greater uncertainty in estimates. Adding a parameter to the model representing receipt of a bivalent vaccine indicated possible greater protection but with wide confidence interval (0.81, 0.29-2.25).

Discussion
We found evidence that third, fourth and fifth dose booster vaccination provide additional short-term protection against SARS-CoV-2 linked mortality amongst LTCF residents, relative to primary vaccination. The pattern of waning of protection appeared to be similar for successive booster doses, stabilising beyond 112 days at 45-75% reduction in risk relative to primary vaccination.
Our findings are consistent with data on fourth dose vaccination of LTCF residents in USA [7] and Canada [8] showing additional short-term protection against SARS-CoV-2 related death. Grewal et al. also found that the additional protection against severe outcomes from fourth relative to third dose waned over time, with negligible protection from 168 days [9]. We are not aware of any publications on fifth dose vaccination of LTCF residents, but fifth dose has been estimated to provide 46.4% additional protection against hospitalisation in the following 3 months compared to four doses in the ≥75y age group in the UK [10].
Our data suggest that the combination of booster vaccination with prior SARS-CoV-2 infection provides particularly strong protection against subsequent mortality from the virus, in line with previous studies in the general population [11]. We are likely to have underestimated the protective effect of prior infection, as we have previously found the cumulative incidence of detected SARS-CoV-2 infection to be substantially higher amongst residents who underwent testing for anti-nucleocapsid antibodies [6]. This suggests that many 'unexposed' residents in our analyses may have in fact been previously infected, although the prevalence of prior infection may be lower in residents who were admitted to care homes in the second half of 2021 and 2022 compared to those resident since 2020. Underestimation of prior infection is unlikely to have had a substantial impact on our estimates of protection provided by booster vaccination, given that the impact did not appear to differ by prior infection status, if we can assume there was not a strong association between undetected prior infection and booster uptake in the LTCF setting.
A limitation of our study is that we lacked data on comorbidities or frailty level of individuals included, which may represent unmeasured confounding if associated with booster uptake. Another limitation is that older residents of LTCFs are a frail population with very high background rates of mortality and it is likely that a substantial proportion of SARS-CoV-2 related deaths in our analysis represent deaths 'with SARS-CoV-2' rather than directly caused by the virus, although attribution of a single cause of death is often not clear in this context [12].
It is possible that the primarily bivalent fifth dose vaccination provided some additional long-term protection, but the pattern of reduction in risk over time did not differ markedly from that observed for prior booster doses. This is consistent with data from the general population in the USA [13], perhaps due to the fact that different Omicron sub-lineages were circulating by the time that bivalent vaccines based on BA.1 lineage were rolled out [14].
We provide evidence that successive booster doses provide additional short-term protection against SARS-CoV-2 related mortality, but lack of sustained benefit from fourth or fifth dose vaccination relative to initial booster dose. These findings raise important questions for policymakers regarding the likely effectiveness and cost-effectiveness of future rounds of SARS-CoV-2 booster vaccination and highlight the continued need to monitor vaccine effectiveness in this vulnerable population.

Declaration of Conflicts of Interest
LS reports grants from the Department of Health and Social Care during the conduct of the study and is a member of the Social Care Working Group, which reports to the Scientific